J Immunol. 2021 Jul 01;207(1):115-124. doi: 10.4049/jimmunol.2100115. Epub 2021 Jun 18.

TLR and IKK Complex-Mediated Innate Immune Signaling Inhibits Stress Granule Assembly.

Journal of immunology (Baltimore, Md. : 1950)

Parimal Samir, David E Place, R K Subbarao Malireddi, Thirumala-Devi Kanneganti

PMID: 34145059 DOI: 10.4049/jimmunol.2100115

Abstract

Cellular stress can induce cytoplasmic ribonucleoprotein complexes called stress granules that allow the cells to survive. Stress granules are also central to cellular responses to infections, in which they can act as platforms for viral sensing or modulate innate immune signaling through pattern recognition receptors. However, the effect of innate immune signaling on stress granules is poorly understood. In this study, we report that prior induction of innate immune signaling through TLRs inhibited stress granule assembly in a TLR ligand dose-dependent manner in murine bone marrow-derived macrophages. Time course analysis suggests that TLR stimulation can reverse stress granule assembly even after it has begun. Additionally, both MYD88- and TRIF-mediated TLR signaling inhibited stress granule assembly in response to endoplasmic reticulum stress in bone marrow-derived macrophages and the chemotherapeutic drug oxaliplatin in murine B16 melanoma cells. This inhibition was not due to a decrease in expression of the critical stress granule proteins G3BP1 and DDX3X and was independent of IRAK1/4, JNK, ERK and P38 kinase activity but dependent on IKK complex kinase activity. Overall, we have identified the TLR-IKK complex signaling axis as a regulator of stress granule assembly-disassembly dynamics, highlighting cross-talk between processes that are critical in health and disease.

Copyright © 2021 by The American Association of Immunologists, Inc.

Publication Types

• Journal Article
• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't